Claims
- 1. A compound of formula I whereinR1 and R2 are optional substituents and independently represent C1-6 alkyl, C2-6 alkenyl C2-6 alkynyl, halogen C1-3 perfluoroalkyl, (CH2)mAr1. (CH2)mHer1, (CH2)mCONR7R8, (CH2)mCO2R8, O(CH2)qCO2R8, (CH2)mCOR8. (CH2)mOR8. O(CH2)pOR8. (CH2)mNR7R8, CO2(CH2)qNR7R8, (CH2)mCN, S(O)nR8, SO2NR7R8, CONH(CH2)mAr1 or CONH(CH2)mHer1; R3 represents H, C1-6 alkyl, (CH2)pNR9R10, SO2R10, SO2NR9R10, (CH2)mCOR10, C2-6 alkenyl, C2-6 alkynyl, (CH2)mCONR9R10, (CH2)mCO2R10, (CH2)pCN, (CH2)pR10 or (CH2)pOR10; R4 and R9 independently represent H or C1-6 alkyl; R7 represents H, C1-6 alkyl or C1-6 alkoxy; R5 represents H or OH; R6 represents methylenedioxyphenyl, alkoxy and halogen, R8 and R10 independently represent H, C1-6 alkyl, Ar2 , Het2 or C1-6 alkyl substituted by Ar2 or Het2; Z represents CO2H, COHN(tetrazol-5-yl), CONHSO2O(C1-4alkyl), CO2Ar3, CO2(C1-6 alkyl), tetrazol-5-yl, CONHSO2Ar3. CONHSO2(CH2)qAr3 or CONHSO2 (C1-6alkyl); m represents 0, 1, 2 or 3; n represents 0, 1 or 2; p represents 2, 3 or 4; q represents 1, 2 or 3; Ar1-3 independently represent phenyl, naphthyl, or an aromatic heterocycle having 5 ring members 2 to 4 which are selected from N, S and O, which aromatic heterocycle is optionally fused to a benzene ring, and which phenyl group is optionally fused to an aromatic heterocycle as defined immediately above, the group as a whole being optionally substituted by one or more groups falling within the definition of R1 above; and Het1 and Het2 independently represent a non-aromatic heterocycle having 5 ring members 2 to 4 of which are selected from N, S and O, which group is optionally substituted by one or more groups falling within the definition of R1 above, and is further optionally substituted by ═O or ═S; or a pharmaceutically acceptable salt thereof.
- 2. A compound as claimed in claim 1, wherein R1 represents halogen, (CH2)mCONR7R8, (CH2)mCO2R8, (CH2)mCOR8, (CH2)mOR8 or (CH2)mCN.
- 3. A compound as claimed in claim 1, wherein R2 is absent.
- 4. A compound as claimed in claim 1, wherein R3 represents H, C1-6 alkyl, or (CH2)pOR10.
- 5. A compound as claimed in claim 1, wherein R4 represents H.
- 6. A compound as claimed in claim 1, wherein R5 represents H.
- 7. A compound as claimed in claim 1, wherein R6 represents methylenedioxyphenyl.
- 8. A compound as claimed in claim 1, wherein Z represents CO2H or CONHSO2Ar3.
- 9. A pharmaceutical formulation comprising a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
- 10. A method of treatment of restenosis, renal failure, pulmonary hypertension, benign prostatic hypertrophy, congestive heart failure, stroke, angina, atherosclerosis, cerebral and cardiac ischaemia or cyclosporin induced nephrotoxicity, which comprises administering a therapeutically effective amount of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.
- 11. A process for the production of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable thereof, which comprises:(a) when R5 represents H, reaction of a compound of formula IIA, wherein R1-4 are as defined in claim 1, with a compound of formula III, wherein R6 and Z are as defined in claim 1, in the presence of a Lewis acid or trifluoroacetic acid, and a tri(C1-6alkyl)silane;(b) when R5 represents OH, reaction of a compound of formula IIA, as defined above, with a compound of formula III, as defined above, in the presence of a Lewis acid; (c) when R3 represents H and R5 represents H, treatment of a compound of formula IIB, wherein R1, R2 and R4 are as defined in claim 1, with a Grignard reagent, followed by reaction with a compound of formula III, as defined above, followed by treatment with a Lewis acid or trifluoroacetic acid, and a tri(C1-6alkyl)silane;(d) when R3 represents H and R5 represents H, treatment of a compound of formula IIB, as defined above, with a Grignard reagent, followed by reaction with a compound of formula IV, wherein R6 and Z are as defined in claim 1, and Hal represents halogen;(e) when R5 represents H, reaction of a compound of formula IIA, as defined above, with a compound of formula IV, as defined above, in the presence of a hindered, non-nucleophilic base; (f) reacting a compound of formula I, in which R1 represents Br, with CO gas in the presence of a palladium catalyst and a reducing agent, to provide the corresponding compound of formula I in which R1 represents CHO; (g) reacting a compound of formula I, in which R1 represents Br, with CO gas in the presence of a palladium catalyst and a C1-6 alkanol, to provide the corresponding compound of formula I in which R1 represents CO2(C1-6 alkyl); (h) coupling a compound of formula I, in which Z represents CO2H, with a compound of formula VI. H2NSO2Ar3 VI wherein Ar3 is as defined in claim 1, to provide the corresponding compound of formula I in which Z represents CONHSO2Ar3; or(i) reacting a compound of formula I, in which R1 represents Br, with an alkyl lithium reagent and quenching with dimethylformamide or carbon dioxide to give a corresponding compound in which R1 represents CHO or CO2H respectively; and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable derivative thereof or vice versa.
Priority Claims (1)
Number |
Date |
Country |
Kind |
9609641 |
May 1996 |
GB |
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CROSS-REFERENCE TO RELATED APPLICATIONS
This is a divisional application of U.S. Ser. No. 09/414,361, filed on Oct. 7, 1999, now U.S. Pat. No. 6,136,843, which is a divisional application of U.S. Ser. No. 09/147,096, filed on Oct. 5, 1998, now U.S. Pat. No. 6,107,945 which is the National Stage of International Application No. PCT/EP97/01882, field internationally on Apr. 11, 1997, which claims priority to GB 9609641.7 field on May 9, 1996.
US Referenced Citations (5)
Foreign Referenced Citations (2)
Number |
Date |
Country |
0617001 |
Sep 1994 |
EP |
9414434 |
Jul 1994 |
WO |